A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety, and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults (MTN-026)

Abstract

Dapivirine (DPV), formulated as vaginal ring, demonstrated HIV risk reduction. MTN-026 explored DPV, formulated as rectal gel, for safety, pharmacokinetics (PK), and acceptability. HIV-uninfected men and women aged 18-45 years were enrolled at United States and Thailand sites and randomized 2:1 to receive DPV 0.05% or placebo gel via rectal applicator. A single-dose phase was followed by seven observed daily doses. Plasma and fluid and tissue from both rectum and cervix were collected at baseline and after the final dose over 72 h for PK, ex-vivo HIV-1 biopsy challenge, histology, and flow cytometry. Twenty-eight participants were randomized; 2 terminated early; 9 were female and 19 male; 12 were white, 11 Asian, 4 black, and 1 other race/ethnicity. Mean age was 28.5 and 34.2 years in the DPV and placebo arms, respectively. Thirty adverse events occurred (all Grade 1 or 2, except one unrelated Grade 3) without study arm differences. DPV rectal tissue concentrations [median (interquartile range)] 0.5-1 and 2 h after a single dose were 256 ng/g [below the lower limit of quantification (BLQ)-666] and BLQ (BLQ-600), respectively, then BLQ (BLQ-BLQ) from 24 to 72 h; concentrations following multiple doses were similar. The largest median DPV plasma concentrations were 0.33 ng/mL (0.15-0.48) after one dose and 0.40 (0.33-0.49) after seven doses. The DPV rectal gel was acceptable and without safety concerns. While DPV plasma concentrations were similar to the vaginal ring, rectal tissue concentrations were well below vaginal ring tissue concentrations, suggesting need for reformulation. Clinical trial number: NCT03239483.

Keywords: HIV; HIV prevention; dapivirine; microbicides; rectal.

FIG. 1.

Diagram of dosing schedule and sampling of blood, rectal fluid and rectal tissue for PK endpoint. Specimen sampling done at dosing visits was targeted at 0.5–1 or 2 h after the dosing. Sampling of rectal fluid and rectal tissue specimens was targeted within 30 min of the blood sample. The seven daily doses were spaced by ∼24 h. PK, pharmacokinetic. Color images are available online.

FIG. 2.

CONSORT diagram for the disposition of participants in MTN-026.

FIG. 3.

Median and IQR of the DPV concentration in plasma (pg/mL), rectal fluid (ng/mg), and rectal tissue (ng/mg) after single and multiple doses of gel applied rectally. Horizontal gray dashed lines indicate the DPV assay LLOQ for each matrix (plasma 20 pg/mL, rectal fluid 0.01 ng/mg, and rectal tissue homogenate 0.003 ng/mg). DPV, dapivirine; IQR, interquartile range; LLOQ, lower limit of quantification. Color images are available online.

FIG. 4.

Vertical boxplots of log-10 weight-adjusted cumulative p24 (pg/mL-mg) from rectal tissue biopsies collected after a single or multiple dosing of study product administered rectally, by collection time and study product arm. Individual observations are indicated by yellow (placebo gel) and light blue (DPV gel) open circles. Horizontal bands show IQR (dark gray) and overall range of the weight-adjusted LLOQ for the cumulative p24. Color images are available online.

FIG. 5.

Log-10 cumulative p24 (pg/mL-mg) from four rectal tissue biopsies versus DPV concentration in rectal tissue biopsies collected at the same time, with a linear fit from a mixed effects model (samples with DPV concentration BLQ from participants in the DPV gel arm were imputed a value of LLOQ/2 while samples from participants in the Placebo gel arm were imputed a value of LLOQ/20). The light gray and dark gray regions indicate the range and interquartilc range, respectively, of the LLOQs for the cumulative p24 (horizontal gray bars) and the DPV concentration (vertical gray bars). BLQ, below the lower limit of quantification. Color images are available online.